Phenotypes Associated with This Genotype

Genotype
MGI:5755244

• Allelic Composition: Mfsd2a^tm1Lex/Mfsd2a^tm1Lex
• Genetic Background: B6;129S5-Mfsd2a^tm1Lex/Mmucd

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cardiovascular system

cardiovascular system phenotype ( J:210589 )

N • despite severe BBB leakage defects, brain vascular patterning is normal, with no detectable abnormalities in capillary density, capillary diameter or vascular branching in E15.5, P4 or adult (P70) brains, and normal cortical arterial distribution in adult brains

N • at 6 months of age, brain capillaries show normal morphology (e.g. cell size, nucleus shape, vessel wall thickness, overall basement membrane structure and pericyte attachment) with no signs of cerebrovascular degeneration

impaired blood-brain barrier function ( J:210589 )

• homozygotes exhibit a leaky BBB from E15.5 through to adulthood, as shown by leakage of both 10-kDa and 70-kDa dextran tracers into the cortical parenchyma and individual parenchyma cells, unlike in wild-type controls

• leaky BBB phenotype is not restricted to carbohydrate-based tracers, as shown by injection of two non-carbohydrate-based tracers of different sizes, sulfo-NHS-biotin (~550 Da) and horseradish peroxidase (~44 kDa)

abnormal vascular endothelial cell physiology ( J:210589 )

• following intravenous HRP injection, electron microscopy revealed a dramatic increase in CNS-endothelial-cell vesicular transcytosis that persists from embryonic stages to adulthood

• however, the ultrastructure of endothelial tight junctions is overtly normal in E17.5 and adult (P90) brains

nervous system

impaired blood-brain barrier function ( J:210589 )

• homozygotes exhibit a leaky BBB from E15.5 through to adulthood, as shown by leakage of both 10-kDa and 70-kDa dextran tracers into the cortical parenchyma and individual parenchyma cells, unlike in wild-type controls

• leaky BBB phenotype is not restricted to carbohydrate-based tracers, as shown by injection of two non-carbohydrate-based tracers of different sizes, sulfo-NHS-biotin (~550 Da) and horseradish peroxidase (~44 kDa)

cellular

abnormal vesicle-mediated transport ( J:210589 )

• following intravenous HRP injection, E17.5 CNS endothelium shows a dramatic increase in the number of vesicles, including luminal and abluminal plasma membrane-connected vesicles and free cytoplasmic vesicles

• pinocytotic events are evident by type II lumen-connected vesicles pinching from the luminal plasma membrane

• a >2-fold increase in vesicle number is observed in various locations along the transcytotic pathway

• at P90, the HRP reaction product is found in vesicles invaginated from the luminal membrane and exocytosed at the abluminal plasma membrane, unlike in wild-type controls where HRP activity is confined to the lumen with no HRP-filled vesicles

• however, pericyte coverage, attachment to the capillary wall, and pericyte ultrastructure and positioning relative to endothelial cells appear normal